| First Author | Sengupta T | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 18 | Pages | 3885-95 |
| PubMed ID | 21746877 | Mgi Jnum | J:175074 |
| Mgi Id | MGI:5142340 | Doi | 10.1128/MCB.05089-11 |
| Citation | Sengupta T, et al. (2011) Hypoxia-Inducible Factor 1 Is Activated by Dysregulated Cyclin E during Mammary Epithelial Morphogenesis. Mol Cell Biol 31(18):3885-95 |
| abstractText | Increased cyclin E expression has been identified in human tumors of diverse histologies, and in studies of primary breast cancers, high cyclin E is associated with poor prognosis. We have studied dysregulated cyclin E in epithelial tissues using organotypic cultures of human mammary epithelial cells and a murine model. We unexpectedly discovered that dysregulated cyclin E impairs normal acinar morphogenesis in vitro, and this is associated with the induction of p21(Cip1), p27(Kip1), and cellular senescence. Cyclin E-induced morphogenesis arrest is dependent upon hypoxia-inducible factor 1alpha (HIF-1alpha), which itself is induced by high cyclin E both in cultured mammary acini and in mammary epithelial tissues in a mouse model of deregulated cyclin E expression. We next determined that E2F activity directly regulates and is required for induction of HIF1A by cyclin E. Additionally, we found that cyclin E deregulation in mammary acini decreases, in an E2F-independent manner, expression of the EGLN1 prolyl hydroxylase that regulates HIF-1alpha degradation within the VHL ubiquitin ligase pathway. Together, our findings reveal a direct link between cyclin E and HIF-1 activities in mammary epithelial cells and implicate HIF-1 as a mediator of proliferation-independent phenotypes associated with high cyclin E expression in some human breast cancers. |
